DOORS Syndrome and TBC1D24-related Epilepsy via the TBC1D24 Gene

Variants in the TBC1D24 gene have recently been implicated in a number of neurological conditions with varied clinical presentations.

TBC1D24 variants were identified in patients with focal epilepsy and intellectual disability. Seizure onset occurred at 2 months of age and consisted of focal seizures with eye blinking and facial and hand twitching (Corbett et al. 2010). These seizures persisted throughout life and were sensitive to fever, but were well controlled with medication (Afawi et al. 2013). Mild developmental delay was noted in early development. There was borderline to moderate intellectual disability seen in adulthood, dysarthria, and ataxia. MRI revealed abnormal cortical thickening.

TBC1D24 has also been implicated in patients with progressive encephalopathy. Features included infantile onset myoclonic seizures, dystonia, and psychomotor delay (Guven and Tolun 2013). Variable features included postictal enduring hemiparesis, refractory seizures, bilateral optic atrophy, and macular degeneration. MRI revealed moderate cerebral atrophy and ventricular enlargement, both of which progressively declined as the patient aged. Death was reported in the first decade. Another study identified TBC1D24 variants in siblings with malignant migrating partial seizures of infancy (MMPSI)(Milh et al. 2013). These patients showed infantile onset of tonic-clonic seizures which increased in frequency until they approached status epilepticus. Psychomotor regression was seen after 3 months and was associated with hypotonia, loss of visual contact, and absence of prehension.

More recently, whole exome sequencing studies have identified TBC1D24 as a cause of deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome. The core features seen in TBC1D24 positive DOORS patients are intellectual disability, seizures, deafness, short distal phalanges and small or absent nails (Campeau et al. 2014). MRI in DOORS syndrome patients were heterogeneous, but revealed structural abnormalities in 50% of patients.

In addition to these conditions which feature seizures as a primary symptom, TBC1D24 variants can also cause autosomal recessive and autosomal dominant non-syndromic hearing loss (ARNSHL, ADNSHL) in the absence of seizures (Rehman et al. 2014; Azaiez et al. 2014; Zhang et al. 2014).

DOORS syndrome and TBC1D24-related epilepsy are inherited in an autosomal recessive manner and are caused by variants in the TBC1D24 gene. Pathogenic missense, nonsense, splice site, and frameshift variants have been reported in TBC1D24 (Campeau et al. 2014). TBC1D24 encodes a protein with an N-terminal Tre2/Bub2/Cdc16 (TBC) domain which is shared by other Rab GTPase-activating proteins (Rab-GAPs). The TBC1D24 TBC domain lacks the arginine and glutamine residues required for GAP activity, suggesting it may not act as a Rab-GAP (Corbett et al. 2010). TBC1D24 is expressed in the brain and physically interacts with ADP ribosylation factor 6 (ARF6)- a GTP-binding protein involved in membrane exchange. Studies in rat neurons suggest that TBC1D24 positively regulates radial neuronal migration by maintaining ARF6 in an inactive state (Falace et al. 2014). Many reported variants in TBC1D24 disrupt its interaction with ARF6. Both loss of TBC1D24 function and expression of constitutively active ARF6 result in similar neuronal migration defects (Falace et al. 2014).

In a study of 26 families with DOORS syndrome, pathogenic TBC1D24 variants were identified in 9 (~35%) families (Campeau et al. 2014).

This test provides full coverage of all coding exons of the TBC1D24 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.